Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, characterized pathologically by a perivascular infiltrate consisting predominantly of T cells and macrophages. Although its aetiology remains unknown, several lines of evidence support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Several widely used disease-modifying agents are approved for the treatment of MS. However, these agents are only partially effective and their ability to attenuate the more progressive phases of the disease is not clear at this time. Therefore, there is a need to develop improved treatment options for MS. This article reviews the role of several novel, selective vaccine strategies that are currently under investigation, including: (i) T-cell vaccination (TCV); (ii) T-cell receptor (TCR) peptide vaccination; (iii) DNA vaccination; and (iv) altered peptide ligand (APL) vaccination. The administration of attenuated autoreactive T cells induces regulatory networks to specifically suppress pathogenic T cells in MS, a strategy named TCV. The concept of TCV was based on the experience of vaccination against aetiological agents of infectious diseases in which individuals are purposely exposed to an attenuated microbial pathogen, which then instructs the immune system to recognize and neutralize it in its virulent form. In regard to TCV, attenuated, pathogenic T cells are similarly used to instruct the immune system to recognize and neutralize disease-inducing T cells. In experimental allergic encephalomyelitis (EAE), an animal model for MS, pathogenic T cells use a strikingly limited number of variable-region elements (V region) to form TCR specific for defined autoantigens. Thus, vaccination with peptides directed against these TCR structures may induce immunoregulatory mechanisms, thereby preventing EAE. However, unlike EAE, myelin-reactive T cells derived from MS patients utilize a broad range of different V regions, challenging the clinical utility of this approach. Subsequently, the demonstration that injection of plasmid DNA encoding a reporter gene into skeletal muscle results in expression of the encoded proteins, as well as in the induction of immune responses in animal models of autoimmunity, was explored as another strategy to re-establish self-tolerance. This approach has promise for the treatment of MS and, therefore, warrants further investigation. APLs are molecules in which the native encephalitogenic peptides are modified by substitution(s) of one or a few amino acids critical for contact with the TCR. Depending on the substitution(s) at the TCR contact residues of the cognate peptide, an APL can induce immune responses that can protect against or reverse EAE. However, the heterogeneity of the immune response in MS patients requires further study to determine which patients are most likely to benefit from APL therapy. Other potential approaches for vaccines in MS include vaccination against axonal growth inhibitors associated with myelin, use of dendritic cells pulsed with specific antigens, and active vaccination against proinflammatory cytokines. Overall, vaccines for MS represent promising approaches for the treatment of this devastating disease, as well as other autoimmune diseases.